Clinical assessment cannot differentiate trivial from potentially serious conditions in these patients.⁸ A history of chills, rigors and sweats strongly suggest the presence of a transient or ongoing bacteraemia. Back pain may be a subtle symptom of endocarditis or vertebral osteomyelitis.

It is difficult to distinguish the patient with endocarditis from other drug users with fever due to another cause. Hospitalization of febrile injecting drug users would be prudent if 24-hour follow-up is not possible. Intravenous drug use in the previous 5 days is a predictor of occult major infection, and is an indication for admission to hospital.⁹

Patients with diabetes mellitus

Diabetic patients are more prone to developing certain bacterial infections.¹ A diabetic patient with an unexplained fever is more likely to have an occult bacterial infection than a non-diabetic patient. In general an insulin-dependent diabetic patient, especially if aged over 50, with fever and no obvious source of infection, should be investigated and preferably admitted.

Febrile neutropenic patients

Febrile neutropenic patients (absolute neutrophil count <500/μL, or <1000/μL and falling rapidly) must be hospitalized for intravenous antibiotics regardless of their clinical appearance. Infections may become fulminant within hours in these patients, and the clinical manifestations of their infective illnesses are frequently modified by the underlying disease, therapy received and coexisting problems.

Splenectomized patients

Splenectomized patients with fever must be very carefully assessed because of their increased risk of overwhelming bacterial infection. If the fever cannot be readily explained, admission for intravenous antibiotics is usually indicated.

Other immunocompromised patients

Fever in transplant patients (renal, hepatic or cardiac) and those with HIV infection is not an absolute indication for admission, but the threshold of intervention should be considerably lowered and they are best assessed by their usual treating doctors.

Patients recently discharged from hospital may have hospital-acquired infections or infections caused by multi-resistant organisms. Recent operations or procedures may be a clue to the site of infection.

Clinical pointers: exposure history

Overseas travellers or visitors

Returned travellers or overseas visitors may have diseases such as malaria and typhoid fever that need early diagnosis and treatment. Any fever in a traveller returned from a malaria-endemic area should be regarded as due to malaria until proved otherwise.

Influenza in febrile returned travellers is a concern to EDs worldwide. Outbreaks of avian influenza occur periodically in bird populations throughout Asia. Although the virus does not typically infect humans, direct bird-to-human transmission of H5N1 influenza has been documented. The virus is highly pathogenic, and the mortality of the disease is high. Travellers acquiring influenza overseas may also introduce this infection. Most cases occur within 2–4 days after exposure, but incubation is as long as 8 days. Suspected influenza infection requires isolation and respiratory precautions. The peak season is generally during the winter months, but can vary, especially in the tropics.¹⁰

Although rare, viral haemorrhagic fever in returned travellers represents a true medical emergency and a serious public health threat. Viral haemorrhagic fevers are caused by several distinct families of virus, including Ebola and Marburg, Lassa fever, the New World arenaviruses (Guanarito, Machupo, Junin, and Sabia), and Rift Valley fever and Crimean Congo haemorrhagic fever viruses. Most exist in Africa, the Middle East or South America. Although some types cause relatively mild illnesses, many can cause severe, life-threatening disease. Viral haemorrhagic fever should be considered in any febrile patient who has returned from an area in which viral haemorrhagic fever was endemic, especially if they have come into contact with blood or other body fluids from a person or animal infected with viral haemorrhagic fever, or worked in a laboratory or animal facility handling viral haemorrhagic fever specimens. All these infections have incubation periods of up to 2–3 weeks, so it may be possible to exclude viral haemorrhagic fever on epidemiological grounds alone. Isolation measures should be instituted immediately in these persons.¹¹

Contact with animals

A contact history with animals, either at work or at home, is frequently the clue to a zoonosis, particularly if the illness is a perplexing fever of several days’ duration. The occurrence of multiple cases at work or at home should also make one suspect these infections early.

Contact with meningococcal and Haemophilus meningitis

Close contacts of patients with these infections have a high risk of acquiring the same infections. Early symptoms may be subtle and a high index of suspicion must be maintained.

Clinical pointers: non-specific clinical features (Table 9.1.1)

There are several non-specific clinical features whose presence should suggest the possibility of sepsis. These warrant careful scrutiny even when the patient does not appear toxic. They are by no means specific indicators of serious problems and there will be many false positives. However, ignoring them is frequently the cause of missed or delayed diagnosis of sepsis.

Table 9.1.1 Clinical pointers: non-specific clinical features (‘alarm bells’)

Severe pain in muscles, neck or back

Impairment of conscious state

Vomiting especially in association with headache or abdominal pain

Severe headache in the presence of a normal CSF

Unexplained rash

Jaundice

Severe sore throat or dysphagia with a normal looking throat

Repeated rigors

Severe pain in muscles, neck or back

Severe muscle pain, even in the absence of overt fever, may be an early symptom of meningococcaemia, staphylococcal or streptococcal bacteraemia. It is also a feature of myositis and necrotizing fasciitis.

Impairment of conscious state

A change in conscious state may be the sole presenting manifestation of sepsis, especially in the elderly.

Vomiting

Unexplained vomiting, especially in association with headache or abdominal pain, should raise concern. Vomiting without diarrhoea should not be attributed to a gastrointestinal infection. It is a common symptom of CNS infections and occult sepsis.

Severe headache in the presence of a normal CSF

This is especially important in a person who seldom gets headaches. Severe headache in a febrile patient with normal CSF should not be diagnosed as a viral infection; many focal infections, e.g. pneumonia and bacterial enteritis may also present in this manner. CSF may be normal in cerebral abscess and in the prodromal phase of bacterial meningitis.

Unexplained rash

An unexplained rash in a febrile patient should be regarded as meningococcaemia until proved otherwise, even in the absence of headache or CSF pleocytosis.

Jaundice

Jaundice in the febrile patient is associated with a greatly increased risk of death, admission to ICU and prolonged hospital stay.⁶ Jaundice in a febrile patient is unlikely to be due to viral hepatitis, but occurs in serious in bacterial infections such as bacteraemia, cholangitis, pyogenic liver abscess and malaria.

Sore throat or dysphagia

Severe sore throat or dysphagia with a normal-looking throat is frequently the presenting symptoms of Haemophilus influenzae epiglottitis in adults.

Repeated rigors

Although repeated rigors may occur in some viral infections they should generally be regarded as indicators of sepsis, in particular abscesses, bacteraemia, endocarditis, cholangitis and pyelonephritis.

Clinical pointers: evolution of illness (Table 9.1.2)

How rapidly the illness evolves is often an indication of its severity. Previously healthy individuals do not seek medical attention unless they are worried. Notice should be taken of any person seeking help within 24 hours of the onset of illness, or a person whose illness appears to have progressed rapidly within 24–48 hours (e.g. from being up and about to being bedridden). Similarly, the patient who presents to the ED on more than one occasion over a 24–48-hour period warrants a careful work-up.

Table 9.1.2 Clinical pointers: evolution of illness

Those present early (< 24 hours)

Those presenting with rapidly evolving symptoms

Patients presenting to ED on > 1 occasion over a 24–48-hour period

Step 4: A final caveat

A major concern in the management of undifferentiated fever in adult is missing the diagnosis of meningococcal bacteraemia when the patient does not appear ill on presentation.

There are a number of infections that must be treated rapidly to minimize morbidity and mortality (Table 9.1.3). With the exception of meningococcal bacteraemia, there are usually some clues in the history or physical examination.

Table 9.1.3 Infections requiring urgent treatment

Disease	Clues
Meningococcaemia	Myalgia, rash. May be none
Falciparum malaria	Travel history, blood film
Bacterial meningitis	Headache, change in conscious state, CSF findings
Post-splenectomy sepsis	Past history, abdominal scar
Toxic shock syndromes	Presence of shock and usually a rash
Infections in the febrile neutropenic	Past history, blood film
Infective endocarditis	Past history, murmur, petechiae
Necrotizing soft tissue infections	Pain, tenderness, erythema and swelling in skin/muscle, toxicity
Space-occupying infection of head and neck	Localizing symptoms and signs
Focal intracranial infections	Headache, change in conscious state, neurological signs, CT findings

Meningococcal infection is peculiar in its wide spectrum of severity and variable rate of progression in different individuals (Table 9.1.4). It may be fulminant and cause death within 12 hours, or it may assume a chronic form that goes on for weeks.

Table 9.1.4 Presentations of meningococcal disease

Acute bacterial meningitis ± petechial rash

Localized infection other than meningitis

Fever + petechial rash

Fever + macular rash

Fever + alarm bells

Fever + contact history

Fever alone

When the patient presents with fever and a petechial rash, meningococcaemia can easily be suspected if one remembers the golden rule of medicine that ‘fever plus a petechial rash is meningococcaemia (or staphylococcal bacteraemia) until proved otherwise’. However, only 40% of meningococcal diseases present with a petechial rash.

It is less well known that the early meningococcaemic rash may be macular, i.e. one that blanches with pressure. This is the basis of another golden rule in infectious disease: early meningococcal rash may resemble a non-specific viral rash.

Rarely, meningococcal disease presents with symptoms and signs of a localized infection other than meningitis, e.g. pneumonia, pericarditis or urethritis. These presentations should not pose any management problems.

The risk of missing the diagnosis increases markedly when the patient with meningococcal disease presents with fever and non-specific symptoms without a rash. Abrupt onset of fever and generalized aches may be due to influenza, but it could be due to meningococcaemia.

It is prudent to single out meningococcal disease and ask oneself, Could this patient have meningococcaemia? If in doubt, the safest course is to take cultures, give antibiotics and admit.

Clinical investigation

Most febrile patients seen in the ED justify a fever work-up.

Full blood examination is of limited use. White cell count (> 15 × 10⁹/L), marked left shift, neutropenia or thrombocytopenia are pointers to a possible bacteraemia or occult bacterial infections, but they may also be seen in viral infections.¹² Similarly, non-specific markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate have not been shown to be useful in predicting outcomes for febrile patients in the ED.¹³

Urinalysis and urine culture should be done in febrile adults over the age of 50 unless the pathology clearly lies in another body system. However, if the history does not suggest urinary sepsis and the dipstick urinalysis is normal, then urine cultures are usually negative.¹⁴

A chest X -ray is usually indicated unless a definite diagnosis has been made, e.g. chickenpox, tonsillitis.

Blood cultures should be done in anyone suspected of having bacteraemia, endocarditis or meningitis, in compromised patients with a fever, all febrile patients over the age of 50, and possibly in anyone with an unexplained high fever. It should be noted that only 5% of blood cultures in this setting will be positive, and less than 2% will alter clinical management.¹⁵ In general, a patient considered ‘sick enough’ to warrant blood cultures should be admitted to hospital or followed up within 24 hours.

Disposition

Patients who have any of the following features are in need of resuscitation, followed by work-up and admission: shock, coma/stupor, cyanosis, profound dyspnoea, continuous seizures and severe dehydration.

With few exceptions the following groups of febrile adults should be investigated and admitted:

• Those over 50 years of age.

• Patients with diabetes mellitus.

• Alcoholic patients.

• Injecting drug users.

• Immunologically compromised patients.

• Overseas travellers or visitors.

• Those with ‘alarm bells’ as described in Step 3.

In general there should be close liaison with the admitting unit, and the issue of empirical therapy for septic patients should be discussed. For the dangerously ill, e.g. those with septic shock or bacterial meningitis, antibiotics should be commenced almost immediately.

There is an increasing tendency to start antibiotics in the ED as soon as possible to reduce the length of hospital stay. Time to antibiotic therapy is used as a key performance indicator for the ED, e.g. for febrile neutropenic patients.

Patients who do not require intervention after the basic work-up in the ED are discharged home after a period of observation. Because of the time taken to interview the patient, perform investigations and wait for the results, the patient will usually have been observed for 1–2 hours, and progression or lack of progression may be a help in deciding what to do. During observation one must be aware that the apparent improvement of the patient may be the result of pain relief or a fall in temperature due to antipyretics.

Arrangement must be made for the patient to be reviewed by their general practitioner or at the hospital. This is an essential component of the care of a febrile patient seen in an ED.

There is no easy way of detecting occult bacterial sepsis. The infectious process is a dynamic one, and the doctor must maintain contact with the patient or family during the 24–72 hours following the initial visit.

Patients with fever > 39 °C must be seen within 24 hours. Review by a doctor within 6–12 hours may be necessary in those who have had a lumbar puncture, and is advisable in those who have had blood cultures taken. A verified phone number should be clearly recorded in the medical history.

All febrile patients discharged from the ED should be encouraged to seek review if there is any adverse change to their condition. A patient re-presenting to the ED has provided an opportunity to ensure that they are being managed appropriately and to rectify any errors.

Fever due to most common viral infections will resolve by about 4 days. Many other infections will be diagnosed when new symptoms or signs appear.

If fever persists beyond 4–5 days without any localizing symptoms or signs, a less common infection or non-infective cause should be suspected and the patient should be thoroughly investigated. In this situation the threshold of admission to hospital should be low.

The establishment of ED short-stay units allows fast-track treatment and observation, usually for 24–48 hours, for carefully selected febrile patients who are not suitable for immediate discharge home.

Future research directions

• The subject of undifferentiated fever of short duration in the adult has not been well studied. There are few data on the spectrum of diseases producing this clinical problem.

Controversies

• Whether empirical antibiotics should be given to adult patients with undifferentiated fever of short duration in order to minimize the risk of death from unrecognized sepsis or meningitis is a perennial question, and there are no algorithms capable of directing management of this problem.

• The safe and ideal course of action is to admit for observation all those patients who are ill enough to warrant a blood culture or a lumbar puncture. The limitation of hospital beds precludes this policy, and there will be unnecessary admissions. The introduction of ED short-stay units provides an alternative for selected patients.

References

1 Mellors JW, Horowitz RI, Harvey MR, et al. A simple index to identify occult bacterial infection in adults with acute unexplained fever. Archives of Internal Medicine. 1987;147:666-671.

2 Gallagher EJ, Brooks F, Gennis P. Identification of serious illness in febrile adults. American Journal of Emergency Medicine. 1994;12:129-133.

3 Norman DC, Yoshikawa TT. Fever in the elderly. Infectious Disease Clinics of North America. 1996;10:93-99.

4 Fontanarosa PB, Kaeberlein FJ, Gerson FW, et al. Difficulty in predicting bacteraemia in elderly emergency patients. Annals of Emergency Medicine. 1992;21:842-848.

5 Marco CA, Schoenfeld CN, Hansen KN, et al. Fever in geriatric emergency patients: clinical features associated with serious illness. Annals of Emergency Medcine. 1995;26:18-24.

6 Tan SL, Knott JC, Street AC, et al. Outcomes of febrile adults presenting to the emergency department. Emergency Medicine. 2002;14:A22.

7 Wrenn KD, Larson S. The febrile alcoholic in the emergency department. American Journal of Emergency Medicine. 1991;9:57-60.

8 Marantz PR, Linzer M, Feiner CJ. Inability to predict diagnosis in febrile intravenous drug abusers. Annals of Internal Medicine. 1987;106:823-826.

9 Samet JH, Shevitz A, Fowle J, et al. Hospitalisation decisions in febrile intravenous drug users. American Journal of Medicine. 1990;89:53-57.

10 Beigel JH, Farrar J, Han AM, et al. Avian influenza A (H5N1) infection in humans. New England Journal of Medicine. 2005;353:1374-1385.

11 Ufberg JW, Karras DJ. Commentary (viral haemorrhagic fever). Annals of Emergency Medicine. 2005;45:324-326.

12 Wasserman MR, Keller EL. Fever, white blood cell count, and culture and sensitivity: their value in the evaluation of the emergency patient. Top Emergency Medicine. 1989;10:81-88.

13 Van Laar PJ, Cohen J. A prospective study of fever in the accident and emergency department. Clinical Microbiology and Infection. 2003;9:878-880.

14 Sultana RV, Zalstein S, Cameron PA, et al. Dipstick urinalysis and the accuracy of the clinical diagnosis of urinary tract infection. Journal of Emergency Medicine. 2001;20:13-19.

15 Kelly A. Clinical impact of blood cultures in the emergency department. Journal of Academic Emergency Medicine. 1998;15:254-256.

Introduction

Definition

Meningitis is an inflammation of the leptomeninges, the membranes that line the central nervous system, as well as the cerebrospinal fluid (CSF) in the subarachnoid space. It is usually the result of an infection, but can be due to an inflammatory response to a localized or systemic insult.

Classification

Meningitis is usually classified according to the aetiology or location as bacterial, aseptic (viral, tuberculous, fungal, or chemical) or spinal (where the infection specifically affects the spinal meninges).

Aetiology

Bacterial

Bacterial meningitis is a serious cause of morbidity and mortality in all age groups. The causes vary according to age, as shown in Table 9.2.1. Neisseria meningitidis serogroups A and C tend to cause endemic cases of meningitis, especially in Aboriginal populations, whereas serogroup B is more commonly associated with epidemics.¹ There has been an increase in the incidence of penicillin-resistant Streptococcus pneumoniae, especially in children.²

Table 9.2.1 Causes of meningitis

Viral	Bacterial	Other
Echovirus 6, 9,11, 30 Coxsackie viruses A9, A16, B1, B5, B6 Enterovirus 71H Herpes simplex 1 & 2 Cytomegalovirus Varicella zoster Epstein–Barr virus	Neonates (<3 months old): Group B streptococcus Escherichia coli Listeria monocytogenes Coagulase-negative Staphylococcus aureus Pseudomonas aeruginosa	Mycobacterium tuberculosis Cryptococcus neoformans (especially in immunocompromised) Aseptic
	Children (<6 years old): Haemophilus influenzae type b Neisseria meningitidis Streptococcus pneumoniae
	Adults Neisseria meningitidis (especially in young adults) Streptococcus pneumoniae Listeria monocytogenes (especially in adults over 45) Klebsiella pneumoniae Staphylococcus aureus Escherichia coli (in the immunocompromised)

Aseptic

Aseptic meningitis may be either due to an immune response to a systemic infection (usually viral), or to a chemical insult.

Viral

Enteroviruses are the most common cause of meningitis, often in clusters of cases. Herpes viruses often cause meningitis as part of a more generalized infection of the brain (meningoencephalitis), or as part of an immune response to a systemic infection. A generalized viraemia may also cause aseptic meningitis, owing to an immune reaction without direct infection.

Fungal

Fungal causes of meningitis, especially that due to Cryptococcus neoformans, tend to occur in immunocompromised patients, such as those with HIV/AIDS, or those on immunosuppressant medication or cancer chemotherapy. It can occur in immunocompetent individuals as well, particularly the elderly.

Tuberculous

Tuberculous meningitis is rare in industrialized countries, but can occur in all age groups. It tends to follow an insidious course, with a lack of classic signs and symptoms. Diagnosis is often difficult, owing to the low yield from CSF staining, and the 4-week time frame required to culture the organism. Suspicion should be high in patients with immunocompromise or chronic illness. It tends to have a high mortality.

Spinal

Spinal meningitis is usually bacterial and due to direct spread from a localized infection in the spine.

Epidemiology

The epidemiology of meningitis is different for groups according to age, as well as immunocompetence:

• Neonates: Table 9.2.1 shows the main causes of bacterial meningitis in neonates. There is an overall incidence of 0.17–0.32 cases per 1000 live births. There is 26% mortality, which is even higher in premature infants.³

• Children: Until the introduction of Haemophilus influenzae type b (Hib) immunization in the early 1990s, this organism was the major cause of bacterial meningitis in children under 5 years (until 1990, the incidence of childhood Hib meningitis was 26.3 per 100 000 (152 per 100 000 in Aboriginal children)).⁴ Between 1990 and 1996 there was a 94% reduction in the incidence of Hib disease. N. meningitidis and S. pneumoniae remain common causes of both meningitis and generalized sepsis.⁵

• Adults: N. meningitidis and S. pneumoniae are common causes in all age groups, with N. meningitidis predominating in adults under 24 years. Listeria monocytogenes is more common in adults over 45 years. The overall incidence in adults is 3.8 per 100 000 population.⁶ More unusual organisms occur in patients following neurosurgery or chronic illness, such as alcoholism, hepatic cirrhosis, chronic renal failure, and connective tissue disease⁷ (GNRs, coagulase-negative Staphylococcus aureus, Mycobacterium tuberculosis, Klebsiella pneumoniae).

• Patients with HIV/AIDS: Cryptococcus neoformans is relatively common, with an incidence of 5 per million of population, or 10% of HIV-infected patients. Tuberculosis, Listeria, Klebsiella and syphilis are also causes of meningitis in this group, as well as viral causes of meningoencephalitis.⁸

• Tuberculous meningitis occurs in around 2% of patients with TB, and around 10% of HIV-infected patients with TB. It has a poor prognosis, with 20% mortality.

Pathogenesis

Initially, there is colonization of the infectious agent, commonly in the nasopharynx in the case of the enteroviruses and bacteria such as meningococcus and Hib. Other infections may spread from already established foci such as otitis media, or sinusitis (e.g. pneumococcus). There is either haematogenous or local spread to the meninges and subarachnoid space, with inflammation of this area and the production of a purulent exudate approximately 2 hours after invasion of the area. The inflammatory response is initiated by bacterial subcapsular components, such as lipoteichoic acid in S. pneumoniae, a lipo-oligosaccharide in H. influenzae, and other Gram-negative endotoxins. These substances stimulate the release of cytokines such as interleukin-1 and -6, tumour necrosis factor (TNF) and arachidonic acid metabolites, as well as the complement cascade. There is a subsequent increase in neutrophil and platelet activity, with increased permeability of the blood–brain barrier. This response is often worse after the initial destruction of bacteria by antibiotics. If left untreated, fibrosis of the meninges may occur. In viral and aseptic meningitis there is a more limited inflammatory response, with mild-to-moderate infiltration of lymphocytes. In the more chronic causes, such as fungi or tuberculosis, the exudate is fibrinous, the main cells being a mixture of lymphocytes, monocytes/macrophages, and plasma cells. The base of the brain is most commonly affected.

Presentation

History

There are some differences in the history with different causes of meningitis, which may allow an early differential diagnosis to be made. There are no pathognomonic single symptoms or signs for meningitis, so a high index of suspicion is necessary.

The combination of fever, headache, meningism and mental obtundation is found in approximately 85% of cases of bacterial meningitis.⁹ It is also a common pattern in viral or aseptic meningitis, where obtundation is less of a feature. In fungal or tuberculous meningitis these symptoms are much less common (less than 40% of cases of cryptococcal meningitis). Elderly patients or those who have had recent neurosurgery may present with subtle or mild symptoms, and lack a fever.¹⁰

The headache is usually severe and unrelenting. It may be either global, or located in a specific area. The main symptoms of meningism are nuchal rigidity (neck stiffness), and photophobia. The nuchal rigidity is something more than merely pain on movement of the neck. It is clinically important when the patient complains of a painful restriction of movement in the sagittal plane (i.e. forwards and backwards only). Up to 35% of cases have associated nausea and vomiting.

As a general rule, the height of the fever is a poor indication of the possible cause, though the fever may often only be mild in tuberculous or fungal meningitis, or in bacterial meningitis that has been partially treated by antibiotics. The spectrum of mental obtundation can range from mild confusion, to bizarre behaviour, delirium or coma. The severity of obtundation is a good indication of the severity of the illness.

Focal neurological signs occur in around 10–20% of cases of bacterial meningitis, but are also associated with cerebral mass lesions, such as toxoplasmosis or brain abscess. They are also a feature of tuberculous meningitis. Seizures are relatively uncommon (13–30%), but may occasionally be the only sign of meningitis if the patient has been partially treated with oral antibiotics.

There may also be associated systemic symptoms. Myalgias and arthralgias are often associated with viral causes, but may also be the sole presenting symptom in meningococcal meningitis. HIV/AIDS patients may show stigmata associated with that disease.

The course of the illness may also indicate the cause. Meningococcal or pneumococcal meningitis is often characterized by a rapid, fulminating course, often going from initial symptoms to death over an interval of hours. Viral causes tend to be a slower course over days. Fungal or tuberculous meningitis shows a more chronic course over days to weeks, with milder symptoms.

Risk factors for meningitis include the extremes of age, pre-existing sinusitis or otitis media, recent neurosurgery, CSF shunts, splenectomy, immunological compromise, and chronic diseases such as alcoholism, cancer, connective tissue disorders, chronic renal failure and hepatic cirrhosis.

Examination

The physical examination will often reflect symptoms elicited in the history, with fever, physical evidence of meningism, stigmata of AIDS, etc.

As stated above, neck stiffness is only clinically significant when it occurs in the sagittal plane. There will be a restriction of both passive and active movement. Other tests to elicit meningism include Kernig’s sign and Brudzinski’s sign, though these are only present in 50% of adult cases of bacterial meningitis. Kernig’s sign is elicited by attempting extend the knee of a leg that has been flexed at the hip with the patient lying supine and the other leg flat on the bed. The sign is positive if the knee cannot be fully extended due to spasm in the hamstrings. The test can be falsely positive in patients with shortening of the hamstrings, or other problems involving the legs or lumbar spine. In Brudzinski’s sign, flexing the head causes the thighs and knees to also flex. It can also be tested in children by the inability to touch the nose with the flexed hips and knees in the sitting position. These are both late signs.

Focal neurological signs should be a cause for concern, as they can indicate a poor prognosis.

Papilloedema is rare and late, as is a bulging fontanelle in infants, and should alert one to alternative diagnoses.

A rash, often starting as a macular or petechial rash on the limbs, is seen in sepsis due to N. meningitidis and S. pneumoniae. A petechial rash is a particularly serious sign, and is an indication to start antibiotics immediately. A maculopapular rash is also a feature of viral causes.

Investigations

Lumbar puncture

A CSF sample via a lumbar puncture (LP) is an important source of information for making the diagnosis and determining the likely aetiology and treatment. As the procedure may be time-consuming, treatment should not be delayed if there will be more than a 20-minute delay before the lumbar puncture and there is a reasonable clinical suspicion that a bacterial cause is present. Blood cultures should be taken prior to the administration of antibiotics.

Precautions

• Deep coma: A patient with a Glasgow Coma Score (GCS) of 8 or less should have the lumbar puncture delayed until they are more awake. A normal brain CT does not exclude the risk of herniation in this group.

• Focal neurological signs: The patient should have CT first, to exclude a space-occupying lesion, which may increase the risk of cerebral herniation following the lumbar puncture.

• Surgery to the lumbar spine.

• Local skin infection around the lumbar spine.

The main features to note during lumbar puncture are the opening pressure and the physical appearance of the CSF. The sample should be sent for Gram staining, culture, sensitivities, a cell count, and protein and glucose levels. If fungal meningitis is suspected, an India-ink stain and cryptococcal antigen screen should be requested. If tuberculous meningitis is suspected, multiple 5 mL samples of CSF will be required to increase the likelihood of a positive result. If there has been prior administration of antibiotics, a bacterial antigen screen should also be requested.

Turbid CSF is indicative of a significant number of pus cells, and is an indication for immediate administration of antibiotics. The patient should usually rest supine for a few hours after the procedure to prevent a worsening of the headache. This has been known to occur up to 24 hours following the procedure. The evidence for the benefits of enforced rest after lumbar puncture is equivocal.

The pattern of cell counts and glucose and protein levels is shown in Table 9.2.2. This can act as a guide only, and the clinician needs to be guided by the complete clinical picture.

Table 9.2.2 Expected CSF values in meningitis

A leukocyte count (WCC) of more than 1000/μL with a predominantly neutrophilic pleocytosis is considered positive for bacterial meningitis. Ten per cent of cases, especially early in the course of the illness, may have a predominance of lymphocytes. As a general rule, bacterial meningitis is characterized by a raised CSF protein and a low CSF glucose level. The ratio of CSF to serum glucose levels is also lowered. The combination of CSF glucose <1.9 mmol/L, CSF to serum glucose ratio <0.23, CSF protein >2.2 g/L, and either a total WCC >2000/μL or a neutrophil count of >1180/μL has been shown to have a 99% certainty of diagnosing bacterial meningitis.¹¹ Aseptic meningitis will often have cell counts near the normal range. This does not exclude infection with less common agents, such as herpes viruses, or L. monocytogenes.

CT scan

CT scanning of the brain is indicated as a prelude to lumbar puncture in the presence of focal neurological signs, mental obtundation or abnormal posturing. It must be noted, though, that a normal CT does not exclude the risk of cerebral herniation in bacterial meningitis,¹² and therefore those with the above signs should have lumbar puncture delayed until they are conscious and stable.

Microbiology

Apart from microscopy and culture of CSF, there are a number of other methods that may allow the causative organism to be identified.

Skin lesion aspirate

In cases where a petechial rash is present, Gram staining or culture from some of the skin lesions may yield the causative organism. This has a reported sensitivity of 30–70%.

Throat swab

Throat swabs are useful in identifying a bacterial cause spread by nasopharyngeal carriage, and should be performed in a case of suspected bacterial meningitis.

Polymerase chain reaction

This potentially allows identification of the causative organism, and even the serotype for organisms such as meningococcus. The test can be performed on CSF or EDTA blood samples, and may remain positive for up to 72 hours after the commencement of antibiotics. In CSF the reported sensitivity is 89% with a specificity of 100%, and in blood a sensitivity of 81% with a specificity of 97%.¹³

Serology

Tests to detect IgM to specific organisms are available for meningococcus and some viruses. For meningococcus, the test has a sensitivity and specificity of 97% and 95%, but is only reliable in adults and children over 4 years old, and takes 5–7 days after onset of the illness to reach diagnostic levels.

Antigenic studies

Latex agglutination, immunoelectrophoresis or radioimmunoassay techniques can be used to screen for antigens from S. pneumoniae, Hib, group B streptococcus (S. agalactiae), Escherichia coli K1, N. meningitidis and C. neoformans. The tests can be performed on serum, CSF or urine. Serum or urine samples tend to allow greater sensitivities (around 96–99%) than CSF (82–99%). The test is no more sensitive in untreated cases than either a positive Gram-stain or the presence of CSF pleocytosis.¹⁴ The main purpose of antigenic studies is in allowing rapid identification of the causative organism in cases confirmed by the CSF findings, or in cases where partial treatment with antibiotics renders the CSF sterile on culture. In many laboratories, these tests have been superseded by PCR methods.

General investigations

FBC, UEC, blood cultures, ESR and a throat swab can assist in building an overall picture.

Blood cultures should be taken prior to parenteral antibiotics, especially in patients where lumbar puncture has been delayed. One study found that blood cultures grew the causative organism in 86% of proven cases of bacterial meningitis, and that the combination of blood culture, CSF Gram staining and antigen testing identified the cause in 92% of cases.¹⁵

Management

Management depends on the likely causative agents, as well as the severity of the illness.

General

Patients should rest in bed, particularly following a lumbar puncture. A quiet, darkened room will be beneficial to those with headache or photophobia. Simple analgesics may be used to treat the headache, with or without codeine. Opiates may be required in severe headache.

Sedation may be necessary if the patient is very agitated or delirious. Suitable drugs are diazepam 5–10 mg i.v. or midazolam 2–10 mg i.v. or i.m., with or without the addition of a antipsychotic such as haloperidol 5–20 mg i.v. or i.m., or chlorpromazine 12.5–50 mg i.v. or i.m.

Seizures should be treated appropriately, initially with a benzodiazepine, then maintenance with phenytoin or phenobarbitone. Meningitis can occasionally be associated with status epilepticus, which should be treated in the standard way.

Patients with raised intracranial pressure may need pressure monitoring, and measures to reduce the pressure, such as nursing the patient 30° head up, and the administration of hyperosmotic agents such as mannitol. Hyperventilation is controversial, as it may reduce intracerebral pressure at the expense of reduced cerebral perfusion. Obstructive hydrocephalus requires appropriate neurosurgical treatment with CSF shunting.

If septic shock has intervened, it should be treated in the usual way, with i.v. fluids and inotropes.

Antimicrobials

The choice of antimicrobial agent will be determined by the likely causative organism, and is therefore determined primarily by age and immune status. It is important that antibiotic therapy is not delayed by investigations such as lumbar puncture or CT, and should be administered as soon as the diagnosis is made. Table 9.2.3 shows the recommended choice of antimicrobial for different situations and organisms. Table 9.2.4 shows the recommended dosage of each. As a general rule, the combination of a third-generation cephalosporin and benzylpenicillin will cover most organisms in all age groups. It is important to note that there is emerging resistance to penicillins in S. pneumoniae (currently 7.6% of isolates in Australia). If Gram-positive diplococci are found or S. pneumoniae is identified on antigen or PCR testing, vancomycin should be added to the therapy.

Table 9.2.3 Choice of antimicrobial in meningitis